The overall objective of the proposed research project is to discover bioactive marine natural products that lead to novel chemotherapeutics for the treatment of pancreatic cancer. Although eleventh in occurrence, pancreatic cancer is the fourth cause of cancer death in the US, with over 34,000 deaths predicted for 2009. Aggressive new combination chemotherapeutic regimes coupled with surgery have resulted in an overall increase in mean survival rate, but even so, fewer than 5% of patients diagnosed with pancreatic cancer will survive five years post diagnosis. Clearly, novel therapeutics are required to treat pancreatic cancer. During the first performance period of the project we made advancements towards the development of new treatments for pancreatic cancer, including findings such as: the discovery of leiodermatolide, a potent antimitotic agent with selective activity for tumor cells that effects microtubule dynamics but not though direct binding to tubulin; neopeltolide, a polyketide that inhibits mitochondrial ATP synthesis through inhibition of the cytochrome bc1 complex; and the finding that manzamine A can restore anchorage dependent growth in pancreatic cancer cells, block tumor cell migration and re-sensitize the ASPC-1 pancreatic adenocarcinoma cancer cell line to TRAIL induced apoptosis. In this renewal application we seek to continue to use a forward chemical genetics approach to build upon these successes. The Specific Aims of the proposed research are: 1. To assay materials from the HBOI marine specimen frozen repository for their ability to 1.1. modify levels of key proteins that have been identified as aberrantly activated in pancreatic cancers and which lead to cancer cell survival, resistance to apoptosis and resistance to currently available chemotherapeutic agents; and block the proliferation of a panel of pancreatic cancer cell lines 2. To utilize state-of-the-art MS and NMR techniques for rapid and accurate dereplication and structure elucidation of candidate compounds. 3. To elucidate the mode of action of materials discovered during the project and to take those compounds which give the best biological profiles forward into experimental models of pancreatic cancer. HBOI maintains a repository of over 20,000 frozen marine specimens which represent a unique collection of natural products for drug discovery. We will use the cytoblot assay to identify small molecules that target pathways that are aberrantly activated in pancreatic cancers and which lead to poor survival rates in patients. Our initial targets will be: the serine/threonine glycogen synthase kinase-32 (GSK-32) which has been shown to activate nuclear factor-kB (NF-kB) transcription in pancreatic cancer cells leading to cell survival and proliferation; and the MAP kinase members P-MEK and P-ERK which are constitutively activated leading to cell survival, invasion and resistance to apoptosis. We will also continue to screen materials against a panel of pancreatic cancer cell lines. Animal models will be conducted at MD Anderson, Orlando. PUBLIC HEALTH RELEVANCE: This project will continue our past successes and lead to new, urgently needed chemotherapeutics for the treatment of pancreatic cancer. The compounds discovered under this project may be used as drugs themselves, modified to provide drugs with improved pharmacological properties or be used as biochemical tools to further understand pancreatic cancer.